tbuckley/cabot-search huggingface dataset:
CTIM-05. FINAL RESULTS OF 2-THE-TOP: A PILOT PHASE 2 STUDY OF TTFIELDS (OPTUNE) PLUS PEMBROLIZUMAB PLUS MAINTENANCE TEMOZOLOMIDE (TMZ) IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM)
Authors: David Tran, Ashley Ghiaseddin, Dongjiang Chen, Son Le, Maryam Rahman
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION TTFields induce anti-tumor immunity via type-1 interferon (T1IFN) pathways of the STING and AIM2 inflammasomes. Thus, TTFields may synergize with immune checkpoint inhibitors to prolong survival in GBM. METHODS We enrolled 26 ndGBM patients in a pilot phase 2 study combining TTFields, pembrolizumab and maintenance TMZ. Primary endpoints were PFS versus case-matched controls of TTFields plus TMZ in the EF-14 study and immune signatures by multiomics of PBMCs and tumors. Secondary endpoints included toxicity and OS. RESULTS The median age was 60.5 years. Fourteen (54%) had biopsy only or partial resection. Nineteen (73%) had unmethylated MGMT and 3 (11.5%) had an IDH mutation. As of 2/16/22, 7 (27%) were progression-free and 14 (54%) were alive with median follow-up of 16.8 months. Median PFS was 12.1 months versus 7.9 months in a case-matched control cohort of 26 patients (HR = 0.456; 95% CI: 0.222-0.937; P = 0.015). Twelve-month PFS was 52.4% (95% CI: 31.4-69.6%) versus 20.4% (95% CI: 5.5-41.7%) in controls; P = 0.012. Six of 15 (40%) patients with measurable disease achieved partial or complete response. Median OS was 25.2 months versus 15.9 months in controls (HR = 0.382; 95% CI: 0.168-0.861; P = 0.078). Two-year OS was 57.8% (95% CI: 33.7-75.9%) versus 19.2% (95% CI: 7.0-36.0%) in controls; P = 0.002. In a Cox regression analysis adjusting for key prognostic factors, P-value reached 0.033 for PFS and 0.020 for OS. Molecular analyses confirmed robust T cell activation via the T1IFN trajectory, which highly correlated with TCRαβ clonal expansion (Spearman coefficient = -0.8; P = 0.014), and defined a T cell-based gene signature of TTFields effects. The most common serious adverse events were thromboses, seizures, and metabolic disturbances in 4 (15%), 3 (11.5%), and 2 (8%) patients, respectively. CONCLUSIONS The triple combination demonstrated acceptable toxicity and promising efficacy in ndGBM. Survival and molecular data will be updated.
NCOG-05. A BRAIN METASTASES SURVIVAL MODEL USING AN ENSEMBLE TREE APPROACH
Authors: John Shumway, Xianming Tan, Peter Drossopoulos, Marina Torras, Madison File, Tushar Joshi, Ashley Ruhashya, Theodore Yanagihara, Colette Shen
Journal: Neuro-Oncology (2022)

Abstract PURPOSE/OBJECTIVE(S) The primary purpose of this study is to determine whether a machine learning approach can estimate survival in patients with brain metastases undergoing stereotactic radiosurgery or fractionated stereotactic radiotherapy (SRS/SRT). The secondary purpose is to identify covariates of importance. MATERIALS/METHODS Data were collected for 377 SRS/SRT treatments in 291 patients done between the years 2008-2021. If a patient was treated with more than one course of SRS/SRT within 30 days, they were counted only once. Twenty-five clinically-relevant variables were identified as covariates and the primary outcome of time from brain metastasis diagnoses to death was used to build a random survival forest model. Brain metastasis location was categorized as infratentorial, supratentorial, or both. An 80/20 split was used for training (n = 302) and test (n = 75) sets. Missing data points were imputed using a just-in-time adaptive tree approach. Minimal depth and variable importance (VIMP) approaches were used to identify prognostic factors. Model performance was assessed using time-dependent area under the receiver operating characteristics curve (tAUC). RESULTS Median survival time was 16 months. The most important variables according to minimal depth analysis (depth threshold 5.23) were Karnofsky Performance Status (KPS), extracranial status, age, insurance status, metastases volume, histology, number of metastases, and location. Error rate on the test set was 0.38. tAUC was found to increase continuously over time and at 6, 12, 24, and 36 months was 0.56, 0.63, 0.74, and 0.84 respectively. CONCLUSION An ensemble tree approach can provide good survival prediction for patients with brain metastases undergoing SRS/SRT. Model performance, as measured by tAUC, increases over time suggesting better predictive capability at longer time intervals. Future directions include collecting more data to increase model performance, comparing to other models, and validating with external data.
QOL-09. NAVIGATING DISABILITY INSURANCE FOR PATIENTS DIAGNOSED WITH LOW-GRADE GLIOMA
Authors: Lalanthica Yogendran, Mark Rudolf, Drew Yeannakis, Kathleen Fuchs, David Schiff
Journal: Neuro-Oncology (2022)

Abstract Central nervous system tumors and their treatments can cause neurologic, cognitive, and psychiatric symptoms that restrict a patient’s ability to work. In the United States, a diagnosis of high-grade glioma (grade 3 or 4) medically qualifies a patient for disability benefits through Social Security. Low-grade gliomas can be similarly debilitating, with at least 50% of patients presenting with one or more cognitive deficits and 80% of patients with tumor-related epilepsy. In light of these serious symptoms, it is unsurprising at least half of patients with low-grade glioma do not return to work within one year of diagnosis. Yet a diagnosis of low-grade glioma does not in and of itself qualify patients for disability benefits; the burden of proof is substantially higher. Thus, patients with low-grade glioma require special attention as they seek disability benefits. Here, we outline the process of medical documentation to support disability benefits, Security Disability Insurance (SSDI) and Supplemental Security Income (SSI). We provide a template to assist providers in facilitating the application process for patients with low-grade glioma seeking disability benefits. The provider’s role is not to simply “declare” a patient disabled, but rather to provide comprehensive documentation regarding the patient’s diagnosis, treatment, response to treatment, symptoms, and functional status in the medical record. As cognitive symptoms and seizures are two key sources of disability in low-grade glioma patients, referrals to neuropsychology and epileptology, among other sub-specialties, are key to improve patient care and bolster documentation of the patient’s symptoms in these domains. Likewise, connecting patients with social workers and disability claims representatives can assist them in navigating the complicated application process. Providers are better able to help their patients navigate the disability application process when they understand how disability evaluations work and what key information evaluators seek.
NCOG-33. IDENTIFYING SELF-EFFICACY DIFFERENCES IN ADULT RARE CNS PATIENTS PARTICIPATING IN A NOVEL WEB-BASED NATURAL HISTORY
Authors: Alvina Acquaye, Elizabeth Vera, Alexa Christ, Kathleen Wall, Mark Gilbert, Terri Armstrong
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION A cancer diagnosis can diminish the sense of control and confidence that is essential for self-management of disease-related factors. Perceived control in coping effectively with the negative effects of a diagnosis has been correlated with improved mood, self-regulation, and decreased symptom distress. We looked at the relationship between self-efficacy in managing emotions (SEMEM) and symptom burden and mood-related interference (REM) in patients with rare CNS tumors. METHODS Adult patients (n=166) completed an online survey capturing demographic/clinical characteristics, symptom burden and REM (mood, relations with others, enjoyment of life, scores³ 2= moderate-severe(M-S)) from the MDASI-BT &amp; MDASI-SP and PROMIS SEMEM (t-scores: low=&amp;lt; 40, high &amp;gt; 60). RESULTS Evaluated patients (74% female) had a median age of 45 (19-75). Ependymoma was most common (66%). The time from initial symptoms and surgery was 1-4 years. Low SEMEM was identified in 13%. SEMEM decreased as REM worsened in both locations (Brain: r= -0.61; Spine (r= -0.28). Most brain patients reporting low SEMEM also endorsed M-S REM (93%). Top M-S symptoms among brain patients associated with each SEMEM level included: feeling distressed, sadness, and fatigue. Low SEMEM correlated with a longer time to presenting symptoms among brain patients (r= -0.26) and lower education among spine patients (r=0.29). Interestingly, sex (women 92%) among brain patients was associated with low SEMEM, while high SEMEM patients were more likely to be married (82%). Spine patients not currently on treatment reported high SEMEM. CONCLUSION We found that patients' confidence in managing emotions worsened with severe mood-related interference. Low self-efficacy was linked to prolonged time between symptoms and initial surgery, education, and gender while treatment and marital status were associated with high self-efficacy. Identifying characteristics associated with self-efficacy can lead to targeted behavioral interventions mitigating distress in adjusting to one’s disease.
DNAR-09. THE IMPACT OF MISMATCH REPAIR DEFICIENCY ON HIGH GRADE GLIOMAS IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS; A REPORT FROM THE IRRDC AND THE GLIOMA TASKFORCE
Authors: Logine Negm, Liana Nobre, Julie Bennett, Jiil Chung, Nick Fernandez, Monique Johnson, Melyssa Aronson, Cindy Zhang, Martin Komosa, Vanessa Bianchi, Lucie Stengs, Mary Jane Lim-Fat, Julia Keith, Derek Tsang, Andrew Gao, David Munoz, Lananh Nguyen, Sunit Das, Adrian Levine, Anirban Das, Cynthia Hawkins, Uri Tabori
Journal: Neuro-Oncology (2022)

Abstract Mismatch repair deficiency (MMRD) is a pan-cancer mechanism resulting in universal hypermutation and aggressive cancers that are resistant to chemoradiation yet sensitive to immunotherapy. MMRD mutations can occur somatically or be inherited as a part of Lynch Syndrome or Constitutional Mismatch Repair Deficiency (CMMRD). Although MMRD affects children, adolescents and young adults (CAYA, ages 0-40) with gliomas, its prevalence and impact of germline inheritance is unknown. Given that high microsatellite instability (MSI) is a key characteristic of MMRD, we previously developed a robust low-coverage whole genome-based tool to quantify MSI, which allows for accurate MMRD detection. We are therefore performing a large-scale MMRD screen of CAYA high grade gliomas (HGGs) and utilizing data from the International Replication Repair Deficiency Consortium (IRRDC) to determine the impact of germline mutations in MMRD gliomas. Ongoing data on 346 HGGs from CAYA patients reveals that MMRD is identified in 6% of HGGs and is not present in tumors with pediatric type alterations. Moreover, of MMRD tumors with IDH1 mutations, none harbor 1p/19q co-deletions. Of patients with available information, all are diagnosed with Lynch Syndrome (69%) or CMMRD (31%), with all Lynch Syndrome diagnoses occurring in patients above 18 years of age. Complementary data from the IRRDC on 113 MMRD patients with gliomas reveal that the median age of glioma is 9.7 and 17.5 years in CMMRD and Lynch Syndrome, respectively (p &amp;lt; 0.001). Strikingly, CMMRD gliomas are enriched for secondary polymerase mutations (60%, p &amp;lt; 0.001) and exhibit ultra-hypermutation, while MMRD gliomas with Lynch Syndrome are enriched for IDH1 mutations (32%, p &amp;lt; 0.025) and harbor a lower mutational burden. Our data reveal a high prevalence of MMRD in CAYA HGGs with alarming impact of germline predisposition. These data can support universal screening for MMRD in high grade glioma diagnostics and identify patients for precision therapeutics.
CTIM-14. COMPREHENSIVE BIOMARKER ANALYSIS OF RESPONDERS AND NON-RESPONDERS IN A PHASE IIA TRIAL OF A CMV VACCINE IMMUNOTHERAPEUTIC CANDIDATE (VBI-1901)
Authors: Patrick Y Wen, David A Reardon, Deborah Forst, Eudocia Lee, Teresa Daoud, Tamara Berthoud, Catalina Soare, Francisco Diaz-Mitoma, David E Anderson, Andrew Lassman, Fabio Iwamoto
Journal: Neuro-Oncology (2022)

Abstract Cytomegalovirus (CMV) antigens have been reported in over 90% of GBMs. CD4+ and CD8+ T cells are most frequently directed against the gB and pp65 antigens, respectively, which are immunogenic targets in a CMV-based GBM immunotherapeutic. First-recurrent GBM patients were enrolled, with Karnofsky Performance Status of at least 70, to receive VBI-1901 (a gB/pp65 enveloped virus-like particle [eVLP]) adjuvanted with GM-CSF and given intradermally (NCT03382977). Patients were vaccinated with VBI-1901 every 4 weeks, with serologic immune-monitoring 2 weeks after each vaccination and surveillance brain MRI scans every 6 weeks. Sixteen patients (8 women, 8 men) with a median age of 55 (33-67 yrs) were enrolled into the GM-CSF arm. Seven tumor responses, including two durable partial responses, were observed which led to an 18-month OS rate of 25% and mOS of 56 weeks. Detailed immunological testing was performed to identify potential correlations at baseline and after treatment between biomarkers and tumor responses. Analyses included class I and II HLA typing, modulation of plasma cytokine and chemokine responses, boosting of CMV-specific antibody and IFN-g ELISPOT responses, and modulation of CMV-specific CD4 Tem cells, of which only differential trafficking of the CD4 Tem cells appears to distinguish patients with tumor responses from those with tumor progression. Single cell, RNAseq is underway in an attempt to understand mechanistic differences in these immune cell populations in Tumor Responders vs. Non-Responders. The U.S. FDA granted Fast Track Designation to VBI-1901 adjuvanted with GM-CSF in first-recurrent GBM patients, and an expansion of the ongoing trial with this formulation in this patient population, with the addition of randomization with a contemporaneous control arm, is anticipated to begin in Q3 2022.
STEM-25. IN VIVO FUNCTIONAL GENOMICS IDENTIFIES ESSENTIALITY OF POTASSIUM HOMEOSTASIS IN MEDULLOBLASTOMA
Authors: Jerry Fan, Patryk Skowron, Anders Erickson, Xian Wang, Xin Wang, Xin Chen, Yu Sun, Siyi Wanggou, Xuejun Li, Michael Taylor, Xi Huang
Journal: Neuro-Oncology (2022)

Abstract Distinguishing cancer maintenance genes—i.e. genes essential and specific to tumor survival—from initiation, progression, and passenger genes is critical for developing effective cancer therapeutics. We engineered the Lazy Piggy genetic screening system, which uses a Sleeping Beauty / piggyBac hybrid transposon to dysregulate and later restore gene expression. In vivo spatiotemporal control of Lazy Piggy transposon insertion and remobilization depletes insertions that are non-essential for tumor survival while enriching for maintenance driver insertions. Using this functional genomic approach, we identify potassium channels as a regulator for medulloblastoma, the most common pediatric brain malignancy. Loss of potassium channel Kcnb2 diminishes the pool of medulloblastoma-propagating cells by hampering their replication potential, thereby prolonging the survival of tumor-bearing mice. Mechanistically, Kcnb2 governs potassium homeostasis to regulate plasma membrane tension-gated EGFR signaling, which drives the proliferative expansion of medulloblastoma-propagating cells. Our in vivo functional genomics reveals potassium homeostasis as a tumor maintenance essentiality, establishes a link between potassium channel activity and plasma membrane tension, and defines a mechanism by which ion homeostasis integrates biomechanical and biochemical signaling to promote medulloblastoma aggression.
CTIM-32. FIRST-IN-CHILDREN PHASE 1 TRIAL OF INDOXIMOD-BASED CHEMO-IMMUNOTHERAPY FOR PATIENTS WITH PEDIATRIC BRAIN TUMORS: ANALYSIS OF SAFETY, TOLERABILITY, AND 5-YEAR OUTCOME
Authors: Theodore Johnson, Rafal Pacholczyk, Dolly Aguilera, Ahmad Al-Basheer, Manish Bajaj, Pratiti Bandopadhayay, Zuzana Berrong, Eric Bouffet, Robert Castellino, Kathleen Dorris, Bree Eaton, Natia Esiashvili, Nicholas Foreman, Diana Fridlyand, Cole Giller, Ian Heger, Nadja Kadom, Eugene Kennedy, Neevika Manoharan, William Martin, Colleen McDonough, Rebecca Parker, Vijay Ramaswamy, Eric Ring, Amyn Rojiani, Ramses Sadek, Amy Smith, Chris Smith, Rachel Vaizer, Kee Kiat Yeo, Tobey MacDonald, David Munn
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Recurrent brain tumors are the leading cause of cancer death in children. We conducted a first-in-children, two-institution, Phase 1 open-label dose-confirmation study using a 3 + 3 design, with expansion cohorts, to determine the recommended pediatric dose of the IDO pathway-inhibitor indoximod (NCT02502708). DESIGN/ METHODS Eligible patients were 3-22 years old with either recurrent malignant brain tumor or newly-diagnosed diffuse intrinsic pontine glioma (DIPG). Palliative radiation, surgery or dexamethasone were allowed as needed for patient management. Separate dose-finding arms were performed for indoximod plus temozolomide (200 mg/m2/day orally for 5 days of each 28-day cycle) and for indoximod plus conformal radiation (in patients for whom re-irradiation was planned as standard-of-care). At progression, patients who were otherwise clinically stable were offered crossover to indoximod plus a second-line chemotherapy regimen (cyclophosphamide 2.5 mg/kg/day orally and etoposide 50 mg/m2/day orally for 21 days of each 28-day cycle). RESULTS Between December 2015 and January 2019, the study enrolled 81 brain tumor patients, including newly-diagnosed DIPG (n = 13) or recurrent ependymoma (n = 27), glioblastoma/high-grade glioma (n = 19), medulloblastoma (n = 13), or other CNS tumors ( n= 9). Median follow-up was 52 months (range 39-77 months). No dose-limiting toxicities were observed, and the pediatric indoximod dose was determined (19.2 mg/kg/dose, given twice daily). Indoximod was well tolerated and did not affect the ability to deliver chemotherapy or radiation as planned. Median overall survival was 13.6 months (n = 81). Median overall survival was 34.7 months for the subset of patients who continued indoximod with second-line chemotherapy after progression on indoximod plus temozolomide (n = 18). CONCLUSIONS Indoximod was well tolerated and could be combined with a variety of standard treatments for pediatric brain tumors. Preliminary anti-tumor activity and overall survival suggest that indoximod with standard therapy should be further evaluated in pediatric brain tumors, and potentially other pediatric solid tumors.
RBIO-01. ACTIVATING AN ION CHANNEL PROMOTES RADIATION-SENSITIZING IMMUNE-DRIVEN ANTI-TUMOR ACTIVITY
Authors: Donatien Kamdem Toukam, Debanjan Bhattacharya, Vaibhavkumar Gawali, Laura Kallay, Aniruddha Karve, Pankaj Desai, James Cook, Taukir Ahmed, Trajan Dan Ionascu, Susheela Tridandapani, Daniel Pomeranz Krummel, Soma Sengupta
Journal: Neuro-Oncology (2022)

Abstract Standard-of-care for melanoma brain metastases is moving to stereotactic radiosurgery (SRS) with immunotherapy. Although this combined approach shows improved patient survival, the responses are not durable. SRS can also cause adverse reactions such as radiation necrosis, which can result in significant morbidity and even mortality. Lowering SRS dose without negatively impacting its effectiveness would therefore be highly beneficial clinically. Our published data suggests that when treating syngeneic mouse model B16F10 melanoma tumors, the radiation dose can be reduced and its effectiveness can be improved, by activating intrinsic melanoma GABAA receptor (GABAAR) activity using a novel agent, AMLAL-101. This agent acts to enhance GABAAR mediated chloride transport in melanoma cells, which in turn triggers mitochondrial dysregulation associated with tumor regression in mice. While AMLAL-101 alone reduces tumor growth, combining it with radiation results in near complete regression of the irradiated tumor, as well as shrinking of tumor not in the radiation field due to an immune response, i.e., a potent abscopal effect. AMLAL-101 may also function to regulate immune cell infiltration into the tumor microenvironment. Analysis of AMLAL-101 treated tumors show increased infiltration into the tumor microenvironment of: (1) polyfunctional (TNFα/IFN-γ) CD8+ T cells; and (2) tumor-associated macrophages (TAMs) of the tumor inhibitory M1-phenotype, possibly due to IFN-γ stimulation. We posit that activating GABAAR with AMLAL-101 promotes both a ‘direct’ anti-tumor response and an ‘indirect’, immune-driven anti-tumor activity in metastatic melanoma tumors. AMLAL-101 may address an urgent unmet need for a non-toxic therapeutic that can potentiate radiation and mitigate its toxicity profile to positively impact clinical outcomes of patients with brain metastatic disease treated with radiotherapy.
PATH-29. BIOLOGIC AND CLINICAL SIGNIFICANCE OF NEOPLASTIC AND MYELOID STATES IN DIFFUSE GLIOMAS
Authors: Bharati Mehani, Saleembhasha Asanigari, Hye-Jung Chung, Karen Dazelle, Kenneth Aldape
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Interactions between neoplastic cell characteristics and the immune microenvironment is an important yet understudied area in diffuse gliomas. We examined this by analyzing single cell RNAseq data (n=290,738) from 35 glioma patients (in-house and GSE182109) including 24 IDH-wildtype and 11 IDH-mutant tumors at the single cell level. Cells were assigned to specific classes, including neoplastic cell states and myeloid components, based on established methods. We used these data to develop a signature matrix to deconvolve bulk RNAseq data from TCGA diffuse gliomas. RESULTS Clustering of neoplastic cells revealed 4 cell states: proneural, mesenchymal, proliferative and cancer signaling. Elevated proneural cell state was, as expected, positively correlated with IDH-mutant tumors, and elevated mesenchymal cell state was correlated with IDH wildtype tumors (both p&amp;lt; 0.01, chi-square), Among IDH-mutant tumors, 1p/19q co-deletion was associated with the proneural state. Fourteen distinct myeloid cell subtypes were identified, and among them several were enriched for either microglial or macrophage (or both) markers. We examined relationships of neoplastic cell state with myeloid cell type abundance and significant associations were identified in both IDH-mutant tumors and IDH-wildtype tumors between specific myeloid cell states and myeloid clusters. Among IDH-mutant tumors, 1p/19q-co-deletion status was positively associated with abundance of a specific microglial cell cluster but negatively associated with abundance of 3 other myeloid cell clusters, suggesting substantial microenvironmental differences based on 1p/19q status in IDH-mutant tumors. In survival analyses, a specific myeloid cluster group proved interesting, with increased abundance of this group showing improved survival in both IDH-mutant and -wildtype tumors, in a manner that was enriched in specific neoplastic cell states. Overall, results suggest specific interactions between neoplastic cell characteristics, (cell states, IDH- and 1p/19q status), with myeloid cell and highlight the need of further studies understand the biological significance of the immune cell environment in diffuse gliomas.